Nociceptors are primary sensory afferent (C and Aδ fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH<6) modalities. The lipophillic vanilloid, capsaicin, activates primary sensory fibers via a specific cell surface capsaicin receptor, cloned as the transient receptor potential vanilloid-1 (TRPV1). TRPV1 is also known as vanilloid receptor-1 (VR1). The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of the TRPV1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Thus, the long lasting anti-nociceptive effect of capsaicin has prompted the clinical use of capsaicin analogs as analgesic agents. Further, capsazepine, a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. TRPV1 receptors are also localized on sensory afferents, which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.
The TRPV1 receptor has been called a “polymodal detector” of noxious stimuli since it can be activated in several ways. The receptor channel is activated by capsaicin and other vanilloids, and thus is classified as a ligand-gated ion channel. The TRPV1 receptor activation by capsaicin can be blocked by the competitive TRPV1 receptor antagonist, capsazepine. The channel can also be activated by protons. Under mildly acidic conditions (pH 6-7), the affinity of capsaicin for the receptor is increased, whereas at pH<6, direct activation of the channel occurs. In addition, when membrane temperature reaches 43° C., the channel is opened. Thus heat can directly gate the channel in the absence of ligand. The capsaicin analog, capsazepine, which is a competitive antagonist of capsaicin, blocks activation of the channel in response to capsaicin, acid, or heat.
The channel is a nonspecific cation conductor. Both extracellular sodium and calcium enter through the channel pore, resulting in cell membrane depolarization. This depolarization increases neuronal excitability, leading to action potential firing and transmission of a noxious nerve impulse to the spinal cord. In addition, depolarization of the peripheral terminal can lead to release of inflammatory peptides such as, but not limited to, substance P and CGRP, leading to enhanced peripheral sensitization of tissue.
Recently, two groups have reported the generation of a “knock-out” mouse lacking the TRPV1 receptor. Electrophysiological studies of sensory neurons (dorsal root ganglia) from these animals revealed a marked absence of responses evoked by noxious stimuli including capsaicin, heat, and reduced pH. These animals did not display any overt signs of behavioral impairment and showed no differences in responses to acute non-noxious thermal and mechanical stimulation relative to wild-type mice. The TRPV1 (−/−) mice also did not show reduced sensitivity to nerve injury-induced mechanical or thermal nociception. However, the TRPV1 knock-out mice were insensitive to the noxious effects of intradermal capsaicin, exposure to intense heat (50-55° C.), and failed to develop thermal hyperalgesia following the intradermal administration of carrageenan.
In the course of characterizing analgesic properties of structurally distinct TRPV1 antagonists multiple investigators have observed core body temperature elevating (“hyperthermic”) attributes of these compounds in rodent behavioral models of pain (Swanson, D. M. et al. J. Med. Chem. 2005, 48, 1857; Gavva, N. R. et al. J. Pharmacol. Exp. Ther. 2007, 323, 128; Steiner, A. A. et al. J. Neurosci. 2007, 27, 7459; Tamayo, N. et al. J. Med. Chem. 2008, 51, 2744; Gavva, N. R. et al. J. Neurosci. 2007, 27, 3366). Often modest (0.5° C.), the associated temperature elevation can be considerably more robust (1-2° C.), and also has been reported preclinically in dogs and monkeys (Gavva, N. R. et al. J. Pharmacol. Exp. Ther. 2007, 323, 128; Gavva, N. R. et al. J. Neurosci. 2007, 27, 3366) and in human subjects in the course of clinical trials (Gavva, N. R. et al. Pain 2008, 136, 202). These effects have the potential to be self-limiting; they are generally transient and attenuate with repeat dosing (Gavva, N. R. et al. J. Pharmacol. Exp. Ther. 2007, 323, 128). Since TRPV1 null mice show no deficits in thermoregulation, the temperature effects are considered to be mechanism based (Iida, T. et al. Neurosci. Lett. 2005, 378, 28). Finding that antagonism of TRPV1 elicits increased body temperature is not wholly unanticipated. The channel's canonical agonist, capsaicin, has been known to cause profound hypothermia for more than 130 years (reviewed in Jancso-Gabor. A. et al. J. Physiol. 1970, 206, 495), and more recent work demonstrated that this decreased body temperature is TRPV1-dependent (Caterina, M. J. et al. Science 2000, 288, 306). The response is generally attributed to cutaneous vasodilation and hypersalivation. The extent of hyperthermia elicited by TRPV1 antagonists is independent of route of administration, suggesting that thermal effects associated with modulation of TRPV1 are not primarily autonomic hypothalamic responses. Instead, accumulating evidence suggests that the temperature elevation signaling pathway initiates in the periphery and is triggered by abdominal TRPV1 that induces vasoconstriction and increased thermogenesis (Steiner, A. A. et al. J. Neurosci. 2007, 27, 7459; Gavva, N. R. et al. Pain 2008, 136, 202).
Efforts to understand and separate the nociceptive and thermoregulatory functions of TRPV1 have led to directed research to identify antagonists that afford analgesic benefit without affecting core body temperature (Lehto, S. G. et al. J. Pharmacol. Exp. Ther. 2008, 326, 218). The polymodal character of TRPV1 offers opportunities to examine whether antagonists exhibit distinctive blockade profiles in response to activation by different stimuli (e.g., capsaicin, extracellular protons, heat >42° C., endogenous lipid ligands) that may portend their ability to modulate channel activity with or without hyperthermic effects.
Certain chromane derivatives that are TRPV1 modulators are discussed in the following publications: WO 2007/042906, WO 2008/059339, US 2006/0128689, WO 2007/121299, US 2008/0153871, and WO 2008/110863.
We describe herein TRPV1 antagonists that possess distinctive blockade profiles in response to activation by different stimuli and exhibit little or no hyperthermic effects.